CCM 文件 03/2015

Research on Oncology of

TCM in HKU

香港大學與中醫藥有關的癌症研究工作

馮奕斌 Dr. Feng Yibin Associate Professor, Associate

Director School of Chinese Medicine

The University of Hong Kong

香港大學中醫藥學院，副教授, 副院長

Research on Oncology of TCM in HKU

香港大学中医药治疗肿瘤的研究 Publication/Yr 发表文章数/年

0

3

6

9

12

15

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Increased by year (数量逐年增长)

Improved quality (质量有所提高)

Facts 基礎資料

Type of Study 研究类型

13.75%

7.50%

3.75%

75.00%

Review

Systematic review metanalaysis

Dermatological study

Original study

(綜述) (薈萃分析)

(調查分析)

(原創性研究)

Study Subjects 研究对象

46.43%

30.36%

21.43%

1.79%

Single Compound

Single Herbal Extracts

Formula

Qigong

(單體) (單味中藥提取物)

(複方) (氣功)

Department Contribution

各部门发表研究工作比例

School of Chinese Medicine

School of Biological Science

Department of Chemistry

Centre of Behaviroal health

Molecular Chinese Medicine Laboratory

Department of anatomy

Department of Medicine

Department of Paediatrics and Adolescent Medicine

Department of Obstetrics and Gynecology

Department of Surgery

Department of Nursing Studies

Faculty of Social Science

Department of Pharmacology

Department of Physiology

55.1

%

Cancer Type Distribution

研究涉及的腫瘤類型分佈

41%

23%

15%

Undefined

Liver cancer

Kidney cancer

Breast cancer

Brain tumor

Lung cancer

Ovarian cancer

Colon cancer

Leukemia

Nasopharyngeal Cancer

Undefined Cancer

Type

Liver Cancer (肝癌)

Breast Cancer (乳腺癌)

香港大學中醫藥的腫瘤研究的類型：

1) Research on new drug derived from Chinese medicines for

new treatment. 從中醫藥中開發抗腫瘤新藥. 2) Research on complementary and alternative treatments to

WM. 從中醫藥中開發抗腫瘤補充和替代新療法. 3) Research on Science and art of CM. 研究中醫藥自身抗腫瘤的科學和藝術.

6

Three types of Anticancer CMs 三大類抗癌中藥

• Anticancer candidates in patents of herbal medicinal products 各國來自於中藥及其他草藥的抗癌專利

1. 15 single compounds and 42 extracts derived from single herbs 15個單體和42個單個植物提取物

2. 8 combinations of single compound or formulae 8個單體或複方的組合

3. 17 single compounds, extracts or formulae in phase 1 or II studies 17個單體，提取物或複方在進行一期或二期的臨床試驗

(Feng Y*, Wang N, Zhu M, Feng Y, Li H, Tsao S. Recent progress on anticancer candidates in patents of herbal medicinal products. Recent Pat Food Nutr Agric. 2011; 3(1):30-48)

7

Chinese medicines as an adjuvant therapy for unresectable hepatocellular carcinoma during transarterial chemoembolization: a meta-analysis of randomized controlled trials

中醫藥在肝癌動脈栓塞化療中作為輔助治療的薈萃分析

Identification Potentially relevant article records: n=2802

Screening

Records after removing duplicates:

n=1911 1514 records excluded: Narrative / systematic reviews: n=243 Non clinical trials: n=459 Irrelevant with Chinese medicines / hepatocellular

carcinoma: n=415 No control group: n=18 Not meet the inclusion criteria: n=379

Eligibility

Full-text articles assessed for eligibility:

n=397

330 full-text articles excluded: Non-RCTs: n=101 Intervention, participant, outcomes not

according with inclusion criteria: n=225 Incomplete outcome data: n=3 Duplicate publications: n=1

Included

Studies included in meta-analysis: n=67

Cheung F, Wang XB, Wang N, Yuen MF, Ziea Eric TC, Tong Y, Wong VT, Feng Y* .eCAM 2013 http://dx.doi.org/10.1155/2013/487919 8

Appendix C. The Top 10 most frequently used CMs of the included studies. eCAM 20130718

CM Herb Latin Name (Chinese

Pinyin)

No. TCM Diagnosis Pharmacological Properties

Radix Astragali (黃芪) 35 Qi deficiency 1. Suppresses the oncogenic transformation of cancer cells1;

2. Induces apoptosis2;

3. Induces macrophage, LAK and NK cell activity3, 4;

4. Inhibits T-helper cell type 2 cytokines4.

Poria Cocos (茯苓) 25 Dampness accumulation 1. Induces apoptosis5, 6;

2. Cytotoxicity against cancer cell lines5;

3. Inhibits tumor angiogenesis 7.

Rhizoma Atractylodis

Macrocephalae (白朮)

23 Qi deficiency 1. Induces apoptosis 8, 9

Radix Ginseng (人參) 19 Qi deficiency 1. Induces apoptosis 10, 11;

2. Inhibits tumor cell proliferation 11;

3. Cytotoxicity against cancer cell lines 12, 13;

4. Inhibits tumor angiogenesis 14.

Radix Bupleuri (柴胡) 19 Qi stagnation 1. Induces apoptosis 15;

2. Activates macrophages, NK and LAK cells 16;

3. Down-regulates TNF-α, IL-6 and NF-kB p65 expression 17.

Radix Codonopsis (丹參) 18 Qi deficiency 1. Inhibit cancer cells invasion and migration 18;

2. Enhances T cell, B cell and macrophage production, and

activates macrophages 19.

Semen Coicis (薏苡仁) 15 Dampness accumulation 1. Induces apoptosis 20;

2. Inhibits NF-kB signaling and protein kinase C activity 21;

3. Stimulates T cell proliferation22.

Herba Oldenlandia Diffusa (白花

蛇舌草)

14 Fire toxin 1. Inhibits cancer cell proliferation and induces apoptosis23, 24.

Radix Paeoniae Alba (白芍) 13 Blood deficiency 1. Inhibits angiogenesis and induces apoptosis25, 26.

Rhizoma Curcumae (莪朮) 12 Blood stagnation 1. Inhibits cancer cell proliferation and angiogenesis, induces

cell cycle arrest and apoptosis 27;

2. Inhibits platelet aggregation28.

9

黃連及其黃連素作為新的抗癌藥：傳統應用和現代研究

Tang J, Feng Y*, Tsao S, Wang N, Curtain R, Wang Y. Berberine and Coptidis Rhizoma as novel antineoplastic agents:

A review of traditional use and biomedical investigations. Journal of Ethnopharmacology 2009; 126:5-17.

10

Case Study: Coptis and its formulae

實例:黃連及其複方

• under the category of clearing heat

• 属于清热解毒药

• detoxify, purify liver, improve eyesight, as well as treating eclampsia, epilepsy, tic caused by fire, carbuncle of heat type, pyocutaneous diseases

• 解毒,清肝,明目,用于治疗热毒引起的目赤，口疮等

• Huang Lian Jie Du Tang, Ge Gen Qin Lian Tang, Zuo Jin Wan etc.

• 常用方剂有100多個，諸如黄连解毒汤,葛根芩连汤,左金丸等

Research Strategies (研究策略)

Huanglian Formula黃連複方

Time (min)

Huanglian Extract黃連提取物

Sustained injury長期慢性損傷Acute

Hepatitis急性肝炎

Chronic Hepatitis慢性肝炎

HCC肝癌

Fibrosis 15-40 yrs

纖維化15-40年

Removing damp-

heat, fire and

counteracting

toxicity

Traditional use Biomedical investigationsNovel protection

and antineoplastic

agents for liver

治療肝病新型藥物

傳統用法 現代生物醫學研究

清熱解毒

Huanglian in treating Acute Hepatic Injury

黃連用於治療急性肝損傷

Pathogens

致病因數

Anti-oxidant

抗氧化因數

Huanglian in treating Chronic Hepatic Injury

黃連用於治療慢性肝損傷

Anti-oxidant

抗氧化因數

Inflammation-related

hepatocyte apoptosis

炎症誘導的肝細胞凋亡

Huanglian in treating Hepatocellular Carcinoma

黃連及其複方用於治療肝癌

Huanglian Extract

黃連提取物

Huanglian Formula 黃連複方

Doxorubicin − +

Doxorubicin + +

HLJDD 25mg/kg 50mg/kg

多柔比星

多柔比星＋黃連複方

Example: Huanglian for NPC Treatment

黃連用於鼻咽癌的治療

Suppression of tumorigenicity and growth of NPC

cells by berberine in vivo. Activation of STAT3 was inhibited by

berberine in vivo.

Constitutive activation of STAT3

was downregulated by berberine

in HONE1 cells

Berberine inhibited the IL-6-activated STAT3

in C666-1 and HK1 cells.

Berberine could inhibit the activation of STAT3 induced by IL6-containing

Fibroblast Supernatant (FS). 50 μM of berberine could effectively suppress the FS-

induced STAT3 activation at 4 hr time points.

Quality control of GQLD

GQLD has significant inhibition on the size

of xenografted tumor

gelatinase activity of MMP-2 could be potently

inhibited by 48-hour GQLD treatment in ACHN

and Caki-1 cells.

Radix Scutellariae(Huangqin)is the major active

component herb in GQLD.

Example: Renal Cancer Treatment 葛根芩連湯用於腎癌的治療

Case Study: Spatholobus suberectus (Jixueteng)

實例:雞血藤

SS inhibits invivo tumor growth.

SS induced G2/M arrest and apoptosis to cancer cells

Elevated ROS level induced by SS

Case Study: Spatholobus suberectus (Jixueteng)

實例:雞血藤

(i) LDH-A is a direct target of SS

(ii) Bioactivity-guided fractionation of SS targeting on LDH-A.

(iii)EGC is the active compound in SS

Perspectives 展望

Laboratory study on TCM in cancer treatment soars in recent years, and is expected to achieve greater outcome in future (基础研究仍将继续发展)

We noticed that high quality clinical trial is not yet available, which may require more attention and efforts in future

(中醫藥抗腫瘤特點，臨床應用規範和临床研究值得期待)

Collaborations with local, national and international pharmaceutical company is highly appreciated, which will make our ultimate goal of curing cancer achievable.

(产学研合作是推广中医药肿瘤治疗的关键)

參考文獻 • 論文發表資料根據PubMed統計而來

• 中文文獻(*通訊作者)

1 馮奕斌*, 羅偉權, 朱世清. 從黃連及其複方古今臨床應用，發掘現代臨床新應用. 中國中藥雜誌. 2008, 33(10):1221-1225

2 林小珊, 馮奕斌*. 香砂六君湯合葛根芩連湯治療大腸癌經驗探析.香港中醫雜誌. 2011, 6(3):35-38.

3 林蓓茵, 馮奕斌*. 糖尿病合併膽管癌關係探討及病案分析一例. 香港中醫雜誌. 2013, 8(1):26-29.

4 林蓓茵, 馮奕斌*. 糖尿病合併結直腸癌關係探討及中藥免煎顆粒治療驗案一例. 香港中醫雜誌. 2014, 9(1):31-36

5 馮奕斌*, 朱世清, 羅偉權. 中醫藥抗癌研究及其思考.中國中藥雜誌. 2015, 接受發表.

• 英文文獻 (*通訊作者)

1 Tsang CM, Cheung KC, Cheung YC, Man K, Lui VW, Tsao SW, Feng Y*. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2015 Mar;1852(3):541-51.

2 Wang N, Feng Y*, Tan HY, Cheung F, Hong M, Lao L, Nagamatsu T. Inhibition of Eukaryotic Elongation Factor-2 Confers to Tumor Suppression by a Herbal Formulation Huanglian-Jiedu Decoction in Human Hepatocellular Carcinoma. Journal of Ethnopharmacology, 2015 Feb 17. pii: S0378-8741(15)00103-8.

3 Wang N, Feng Y, Cheung F, Wang X, Zhang ZJ, Feng Y*. A Chinese Medicine Formula Gegen Qilian Decoction Suppresses Expansion of Human Renal Carcinoma with Inhibition of Matrix Metalloproteinase-2. Integrated Cancer therapy 2015 Jan; 14(1):75-85.

4 Wang N, Zhu M, Wang X, Tan HY, Tsao SW, Feng Y*. Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma. Biochim Biophys Acta. 2014 Jun 3. pii: S1874-9399(14)00141-2.

5 Tsang CM, Cheung YC, Lui VW, Yip YL, Zhang G, Lin VW, Cheung K, Feng Y*, Tsao SW*. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts. BMC Cancer. 2013 Dec 31; 13(1):619.

6 Tan HY, Wang N, Tsao SW, Zhang Z, Feng Y*. Suppression of Vascular Endothelial Growth Factor via Inactivation of Eukaryotic Elongation Factor-2 by Alkaloids in Coptidis rhizoma in Hepatocellular Carcinoma. Integrated Cancer therapy 2014 Sep;13(5):425-34.

7 Wang N, Zhu M, Tsao SW, Man K, Zhang Z, Feng Y*. MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma. Mol Cancer. 2013 Oct 8;12(1):119.

8 Wang N, Feng Y*, Zhu M, Siu FM, Ng KM, Che CM*. A Novel Mechanism of XIAP Degradation Induced by Timosaponin AIII in Hepatocellular Carcinoma. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2013; 1833(12):2890-2899.

9 Cheung F, Wang XB, Wang N, Yuen MF, Ziea Eric TC, Tong Y, Wong VT, Feng Y*. Chinese medicines as an adjuvant therapy for unresectable hepatocellular carcinoma during transarterial chemoembolization: a meta-analysis of randomized controlled trials. Evidence-Based Complementary and Alternative Medicine 2013:487919.

10 Wang N, Feng Y*, Zhu M, Chow O, Wang XB, Su W, Tong Yao. A Comparative Study on the Hepatoprotective Action of Coptidis Rhizoma Aqueous Extract and Bear Bile on Carbon Tetrachloride induced Liver Fibrosis in Rats. BMC Complement Altern Med. 2012;12(1):239.

11 Wang N, Zhu M, Tsao SW, Man K, Zhang ZJ, Feng Y*. Up-regulation of TIMP-1 by Genipin Inhibits MMP-2 activities and Suppresses the Metastatic Potential of Human Hepatocellular Carcinoma. PLoS One 2012;7(9):e46318.

12 Feng Y*, Wang N, Ye X, Li H, Feng Y, Cheung F, Nagamatsu T. Hepatoprotective effect and its possible mechanism of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced chronic liver hepatotoxicity in rats. Journal of Ethnopharmacology 2011 Dec 8;138(3):683-90.

13 Wang N, Pan W, Zhu M, Zhanf M, Hao X, Liang G, Feng Y*. Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signaling in human hepatocellular carcinoma cells. British Journal of Pharmacology. 2011;164(2b):731-742.

14 Feng Y*, Wang N, Zhu M, Feng YG, Li HY, Tsao SW. Recent progress on anticancer candidates in herbal medicinal products. Recent patent in Food, Nutrition & Agriculture. 2011, 3(1):30-48.

15 Zhu M, Wang N, Tsao S, Yuen M, Feng YG, Wan Thomas SK, Man K, Feng Y*. Up-regulation of microRNAs, miR21 and miR23a, in human liver cancer cells treated with Coptidis Rhizome aqueous extract. Experimental and Therapeutic Medicine 2011, 2: 27-32.

16 Wang N, Feng Y*, Lau EP, Tsang C, Ching Y, Man K, Tong Y, Nagamatsu T, Su W, Tsao S. F-actin reorganization and inactivation of rho signaling pathway involved in the inhibitory effect of Coptidis Rhizoma on hepatoma cell migration. Integrate Cancer Therapy. 2010, 9(4):354-64.

參考文獻

16 Wang N, Feng Y*, Zhu M, Tsang CM, Man K, Tong Y, Tsao SW. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of cellular biochemistry 2010, 111(6):1426-36.

17 Tang J, Feng Y*, Tsao S, Wang N, Curtain R, Wang Y. Berberine and Coptidis Rhizoma as novel antineoplastic agents: A review of traditional use and biomedical investigations. Journal of Ethnopharmacology 2009; 126:5-17.

18 Tsang CM, Lau Echo PW, Di K, Cheung PY, Hau PM, Ching YP, Wong YW, Cheung Annie LM, Wan Thomas SK, Tong Y, Tsao SW* and Feng Y*. Berberine inhibits RhoGTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells. International Journal of Molecular Medicine 2009; 24:131-138.

19 Ye XS, Feng Y*, Tong Y, Ng KM, Tsao SW, Lau George KK, Sze CW, Zhang YB, Tang J, Shen JG, Kobayashi S. Hepatoprotective effects of Coptidis Rhizoma aqueous extract on carbon tetrachloride-induced acute liver hepatotoxicity in rats. Journal of Ethnopharmacology 2009; 124:130–136.

20 Wang Z, Wang D, Han S, Wang N, Mo F, Loo TY, Shen J, Huang H, Chen J*. Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer. PLoS One. 2013;8(2):e56631. doi: 10.1371/journal.pone.0056631.

21 Wang N, Wang Z, Peng C, You J, Shen J, Han S, Chen J*. Dietary compound isoliquiritigenin targets GRP78 to chemosensitize breast cancer stem cells via β-catenin/ABCG2 signaling. Carcinogenesis. 2014 Nov;35(11):2544-54. doi: 10.1093/carcin/bgu187.